Are you currently (or have you been) in a Clinical Trial?
Comments
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Dear Susan, Cureious, why did you guys come up to a conclusion that Enhertu is not an option? I think it would be quite wise to try Enhertu as it has different payload than Trodelvy, and target is different (Her2 vs Trop2), and it is the only one that has bystander-effect which is super-cool. I am a big believer that her2+ therapies (ADCs in particular) will be eventually used in her2low cases. NGS/blood tests show mutations/expressions but they do not show driving genes:/ I think if IHC shows her2+-, and HR therapies failed, it is quite likely that her2 might be at least one of the main driving expressions. If you have a chance, go for Enhertu. It just beat T-DM1 by miles and miles in Destiny-Breast-03 II line, and not only mOS but also mPFS was not reached after 16 months. Her2low are also doing great on it. Crazy! I'd give everything to get this drug for my wife - unfortunately we'll have it in our healthcare system maybe in 2024 or later:/ Saulius
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Saulius,
My understanding was that the payload for Enhertu and Trodelvy was similar. Enhertu does seem to work for her2 low but there isn't any data about Enhertu after Trodelvy. I have heard that going from Trodelvy to Enhertu may work but not the other way around since Enhertu is stronger.
My previous post that trastuzumab–duocarmazine may not work for me since the antibody is trastuzumab is probably incorrect since Enhertu also utilizes trastuzumab as the antibody and that works for her2-low.
I found an interesting paper about her2-low: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429068/ The article explains that the definition of her2+, i.e., +3 ISH, is based on responses to trastuzumab, the first her2+ therapy. Since that classification, little has been done for the +2 and +1 groups since Trastuzumab was the gold standard.
Appreciate your response. I have definitely kept Enhertu on my list for next treatments. My MO also thought it might work for me.
Hugs, Susan
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Susan my MO just suggested Trodlevy to me and I am triple NEG...why would it be used for her2low...(her2Positivve...)???
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Cure-ious, I was told that I qualified for a clinical trial at my Cancer center. Today I was told I do not. Grrrr.
So, can you help me to check on any for ERPR+HER2- with ESR1 D538g? Preferably in the Dallas Metroplex.
I’ve been at this for five years, mets to liver and lung, and have exhausted all local therapy and most chemotherapy.
I was very excited about the trial for a new SERD type TX but it was for Y537s not the one I have.
Anyone else have this one
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Following up with the conversations on different ADCs, does anyone know anything about CX-2009? It’s a new ADC drugcurrently in phase 2 trials. The antibody in this drug targets CD166, and chemo payload is an anti-microtubule. So this one seems like totally different from Trodelvy or Enhertu.
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Susan & Saulius, I will check on the payloads of the ADCs, but just remember Susan saying that her MO, Hope Rugo, had said you would take one or the other (Enhertu or Trodelvy) but not both. OTOH, those were in the early days and maybe there are some data about this now.
I read that Herceptin did not work out in original trials for Her2low, but of course they are having great results with Enhertu, which makes sense because it is a much stronger drug. I guess if you have Her2-low you are not as sensitive as Her2-positive to anti-Her2 monoclonal as a monotherapy, which makes sense. The Herceptin monoclonal is able to act on its own to kill the cells for Her2-positive cancers, but with Enhertu they coupled the monoclonal to a chemo payload so the killing is way more effective and you don't need a ton of the Her2 antibody on the surface of the cell to be able to attract enough drug to hit it effectively.So its just a matter that the HER2-low needs the more powerful HER2 treatments.
Also, they are making CAR-T for Her2 and I bet that will work for Her2-low? More treatments are coming, so if you are Her2-low, its not just one treatment you can get. Also remember that about half of ER-positive MBCs are Her2-low, at least eventually they get that way, because that is a common way that MBCs become resistant to endocrine therapy- so potentially this will become a big deal for treatment of many ER-positive cancers
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Grannax, There are some limited data suggesting that the ARV-471 PROTAC (bit different from a SERD but does the same thing) that AlabamaDee is taking may be the strongest in that class, and for sure it is working on ESR1 mutants.
https://clinicaltrials.gov/ct2/show/NCT04072952
Unfortunately the existing trial is only in a few places and not Dalls, but new trials will hopefully be added soon, since Pfizer just bought them out. And you want it with combined Ibrance or a CDK4,6 inhibitor. Will check out some other trials, I know it gets harder when you had some chemo- Have you had Enhertu or Trodelvy (these are the ADC chemos)? in clinical trials ER-positive cancers were averaging PFs like 16 months even when for people who had plenty of prior chemos
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Figtree, this report says that CX-2009 is a potent microtubule inhibitor but couldn't be used before as a chemo before because it killed too many normal cells- with the advent of the ADC technology, where they can target the drug to cancer cells that express CD166 (as many do), they are having better luck ; First trials were checking lots of different cancers, they found 5 out of 39 heavily-treated breast cancer patients actually got tumor shrinkage, which is quite promising in phase one where you are mostly trying to figure out the right dosage, presumably more also responded as stable- its moved on to phase 2 now.. Now that they picked a dosage they will also be able to better determine what the side effects of the drug are
https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.1...
The link below is to a trial, they will test this ADC alone for ER-positive cancers and in combination with some immunotherapy for TNBC:
https://clinicaltrials.gov/ct2/show/NCT04596150
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Thank you Cure-ious! You are a blessing to this board!
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Dear Cureious&Susan, I went a bit deeper and Enhertu has same type of payload as Trodelvy (DXd and SN-38 are both topoisomerase I inhibitors), almost same drug to antibody ratios, so also probably a bystander effect, yet DXd is much more potent than SN-38, and its bystander effect is very well proven (https://clincancerres.aacrjournals.org/content/27/14/3970 - this article was freely accessible before and showed amazing pictures of DXd infiltrating nearby, that is not HER2+, cells). Also it really depends how effective a drug can be on HER2 and TROP2 expressions. Say if your cells have more HER2 (which might still be considered her2low for trastuzumab) receptors than TROP2, Enhertu would be much more effective, at least in theory. For sure I don't want to argue with Dr. Hope Rugo - she knows it all much better but knowing Susan is like her2++, it all sort of points to Enhertu... ehm... Saulius
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the latest Breast Cancer Update with Neil Love podcast talks about Her2 low with DrIan Krop. Sept 23. It’s a nice summery of the evolution of treatment for HER 2 and HER 2 low.
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saulius- Very good info to know! But even if we consider Enhertu may be a more effective drug, and that her cancer might have more Her2 expression (to attract Enhertu) as compared with Trop2 (to attract Trodelvy), the fact that she progressed on Trodelvy would indicate the cancer has become resistant to the chemo payload, right? So would probably be better to use a different Her2-directed ADC?
Below link is a recent review of the Her2 ADCs, and some excerpts:
"Given their advanced pharmaceutical properties, next-generation HER2-targeted ADCs have the potential to be active beyond traditional HER2-positive breast cancer and may be effective in cells with low expression of HER2 or ERBB2 mutations, opening a spectrum of new possible clinical applications."
"Of interest, T-DM1 seems to be active in cancers with HER2 mutations, regardless of amplification/expression status—providing an opportunity to expand in a setting of high unmet need"
"T-DXd (Enhertu) has a DAR of 8 (compared T-DM1, which has a DAR of 3.5) and its cytotoxic payload, derived from exatecan, is a potent topoisomerase I inhibitor rather than a microtubule inhibitor. Additionally, T-Dxd incorporates a cleavable linker, thought to be acted upon by cathepsins, lysosomal enzymes which are upregulated in many cancer cells. Relatedly, the payload is membrane permeable, hence capable of exerting the bystander effect, theoretically allowing activity even in tumors with heterogeneous or low expression of HER2. This property is not observed with T-DM1."
They discuss SEVEN next-generation Her2-directed ADCs currently in trials.
Results for Enhertu in HER2-low Cancers: in 54 heavily pretreated patients (median 7.5 prior lines) treated at a dose of 5.4 or 6.4 mg/kg, the ORR confirmed by independent review was 37% (95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 months to not evaluable) and median PFS of 11.1 months (95% CI, 7.6 months to not evaluable)
A similar response rate has been observed in patients treated with SYD985 (a next-gen ADC) where patients with HER2-low MBC, including hormone-receptor positive (N = 32) and hormone-receptor negative breast cancers (N = 17) had ORRs of 27% and 40% respectively
https://breast-cancer-research.biomedcentral.com/a...
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Cure-ious, Thanks for the information.
I thought Trodelvy was only approved for Triple -?
I’ve taken Ibrance four years ago. It failed.
Yes, I’ve had at least six chemos in the metastatic setting.
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So Susan, if you have to look beyond Enhertu, for the HER2-low you could try SYD-985 ADC
SYD-985 was previously granted a fast track designation in January 2018 by the FDA in the last-line for previously treated patients with HER2-positive metastatic breast cancer. The indication was based on the results of a 2 part, phase 1 trial examining the agent, with preliminary results revealing an ORR of 33% and a median PFS of 9.4 months in patients with heavily pretreated HER2-positive or HER2-low breast cancer
This report indicates they finished phase 3 and are submitting for FDA approval by end of the year. https://www.cancernetwork.com/view/trastuzumab-der...
There is also a phase one trial combining this ADC with paclitaxel, that trial takes both Her2-positive and Her2-low, but one cannot have had more than two prior chemos in metastatic setting and is only in Colorado: https://clinicaltrials.gov/ct2/show/NCT04602117
Also there is a phase one trial combining it with a PARP inhibitor, again is for either Her2-positive or Her2-low- but this one is only in UK, Netherlands and Belgium-
https://clinicaltrials.gov/ct2/show/NCT04235101
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Grannax, All the Trodelvy literature is directed for TNBC, however they had good results in a trial for ER-positive MBC, and I guess that Susan must have had it in a trial...
https://pubmed.ncbi.nlm.nih.gov/32946924/
I guess for ADCs, you would want to figure out if your cancer has some Her2 expression so you could try Enhertu?
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I wanted to clarify that Hope said that Enhertu might work after Trodelvy. I'm the one who thought it was unlikely to work given the similar toxic payload.
What scares me about Enhertu is that there are a lot of lung problems associated with it and my lung is in pretty bad shape. That is why, when she first suggested Enhertu rather than Trodelvy, I opted for Trodelvy. Still, I am keeping Enhertu on my list of possible next treatments.
I am very excited about SYD-985. When I look at the latest results, it mentioned both HER2+ and HER2-low patients. One of the eligibility criteria was HER2+ tumor status so how do they have results for HER2-low patients?
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Cure-ious, I’ve had three liver BX and they all said HER 2- She may want another BX and genomic testing.
So, since there are good results in ER+ trials, would I have to be in a trial? Or could I possibly get expanded access?
Susan, were you in a trial? If so, where?
Thank
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Susan, In the write-ups for these recent trials, the eligible category says they are taking all Her2-expressing tumors, either Her2 amplified (as in Her2-positive) or Her2-low (IHC+1 or +2), so they are taking a broader view of what is a Her2 cancer nowadays, and there were Her2-low patients in those trials.
If I were you, I'd put Enhertu over SYD-985 on the to-do list, I was just listening to the side effects, grade 3 eye toxicity is the main one for SYD-985 but there were also some others, and the guy was saying- well this is why it would be a later-line drug... Enhertu will have more breakthrough effect than Trodelvy did, and when you progressed it could have been because TROP-2 protein expression got down-regulated in the cancer cells so the drug was not effectively targeted anymore, which might be one of the more common ways to get progression and nothing to do with the chemo payload, the cancer is presumably still sensitive to that.
The GOOD news for you, with respect to any Her2-ADC, is that the results they post for these trials are for those who had at least two prior Her2 therapies. You haven't had ANY Her2 treatment, so potentially the cancer will respond even better.
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Grannex- when I spoke to my UCSF second opinion MO- she told me I was Her 2 low (2+) based on my original breast tumor. To be in the study for enhertu you needed to have 2 confirmatory biopsies-she was not sure a bone bx would be accepted and so far I am bone only for Mets
She did tell me that none of the original her ++ (2+) were negative on re biopsy but, some of the 1+ were negative on re- biopsy. As Cure-ious and the podcast says- probably 50+ % of people are Her2 low. The Herceptin doesn’t work on Her2 low so they were labeled negative.
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Cure-ious and Saulius,
You have really given me hope that I'm not at the end of my treatment runway yet. I agree that Enhertu is my best choice for next treatment. Maybe Enhertu can keep me from progressing long enough to get on SYD-985. Grade 3 eye toxicity sounds pretty scary but hopefully they will figure out a way to preempt that as they have done with ILD for Enhertu. These next gen ADCs have opened up a lot of possibilities for us.
I've been feeling a lot of anxiety lately and am starting to feel that melting away.
Hugs, Susan
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For Grannax and others this may help -- from the Metavivor website re if you cannot find a trial (also posted on Liver Mets)
WHAT IF I CANNOT PARTICIPATE IN THE CLINICAL TRIAL AND I AM OUT OF OPTIONS?
Two programs are available for you to explore if you are out of treatment options: Right to Try and Compassionate Use. Metavivor patient advocates worked very hard to pass the Federal Right To Try act in 2017 and 2018. In 2018, the Federal Right To Try Act was signed into law. It isn't widely used because most patients are not aware of it.
WHAT IS RIGHT TO TRY?
Right-to-try laws are U.S. state laws and a federal law that were created with the intent of allowing terminally ill patients access to experimental therapies (drugs, biologics, devices) that have completed Phase I testing but have not been approved by the Food and Drug Administration (FDA).
This law is another way for patients who have been diagnosed with life-threatening diseases or conditions who have tried all approved treatment options and who are unable to participate in a clinical trial to access certain unapproved treatments.
Patients should first consult with their physician and that their physicians consult with the sponsor of the investigational drug or biological product. The sponsor is in the best position to provide information about whether the drug or biological product meets the criteria to be considered an eligible investigational drug for use under the Right to Try Act.
WHAT IS COMPASSIONATE USE?
Sometimes clinical trial enrollment is not possible for those living with metastatic breast cancer. Patients may therefore seek access to investigational medicines outside of a clinical trial.
Sometimes called "expanded access", compassionate use is a potential way for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. This is a potential solution when patients run out of treatment options but do not have access to a clinical trial.
Other clinical trials test ways to find a disease early, sometimes before there are symptoms. Still others test ways to prevent a health problem. A clinical trial may also look at how to make life better for people living with a life-threatening disease or a chronic health problem.
Before the U.S. Food and Drug Administration (FDA) approves a clinical trial to begin, scientists perform laboratory tests and studies in animals to test a potential therapy's safety and efficacy. If these studies show favorable results, the FDA gives approval for the intervention to be tested in humans.
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A very interesting discussion guys, thank you. I see many delivery problems with drugs, so might be that drugs are good for us in theory but they are not delivered to sites we need in our bodies. I read in one article that ~0.1 % of conventional chemo (that is 1/1000!) is delivered to the disease, the rest is absorbed by our bodies - if they could increase delivery up to 1-2 % (so ten-fold), any of conventional chemos would produce cures in metastatic setting. Same with my wife: all NED except for infraclavicular lymph nodes. Biopsy showed ER 0%, PR 0%, HER2 100%. Trastuzumab+Pertuzumab work everywhere else but not there - why? Because for some reason they are not delivered there:/ Might be that the best drug is not the one that fits genomic profile but the one that is best delivered which is impossible for science to know today. That is pretty sad when you hear you could be easily cured by conventional chemo if it would be well delivered to tumors. BBB, drug molecules too large, our blood vessels are too small or tissue damaged by radiation... all sorts of those problems... Anyway, I wanted to say that you guys in USA are very lucky to have access to so many options and newest drugs. That is so cool... Saulius
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Grannax, Circling back to you! What are you most wanting in a clinical trial?
Here is a trial at UT-Southwestern (is that near you?) for a SERD, and it works on ESR1 mutants. However, I am confused that you were rejected from a trial based on not having the "right" ESR1 mutation, and wonder if that means that the mutant you have functions the same as the wild-type estrogen receptor and is not therefore the cause of your progression?
https://clinicaltrials.utswmed.org/studies?utf8=%E...
Here is one I like even better, also at UT-Southwestern, it is a SERD and you can combine it with various other drugs, Everolimus, Abemaciclib or Piqray
https://www.clinicaltrials.gov/ct2/show/NCT0418854...
The thing with these trials is they will work with an ESR1 mutant but also with normal estrogen receptor, so it will work either way...
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Cure-ious. UTSW is saying they have screened me and I’m not eligible for any of their trials.
The one I wanted was for ESR1. There are two ESR1 mutations. Their trial is for the one that starts with Y, mine starts with D. I should have them memorized but I don’t. Plus I have had about six chemos in the metastatic setting.
We don’t have time to wait on expanded access.
My PET report is horrible. ( I wrote on the liver mets thread) There is spread to other areas, rib, lymph nodes near my heart and esophagus, lung is worse, liver says innumerable and uptake is 10-11.
MO is checking at Baylor for any trials I would qualify for if not she’ll try Exempra and Xeloda together
Thanks for your help
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Grannax, Ixempra and Xeloda would be a good choice.
One trial at Baylor you could consider involves a new drug (ORIN1001), which is being tested for ER-positive MBC or TNBC, either alone or in combination with Abraxane. The drug is an inhibitor of the IRE1 enzyme, which is a critical partner for MYC-expressing cancers. Inhibitors of IRE1 block tumor cell growth and also improve access of the tumor microenvironment to infiltrating T cells. This was developed at Baylor, and here is their description:
Limited sensitivity to chemotherapy and an immunosuppressive tumor microenvironment drives breast cancer mortality in HER2 negative breast cancer. We have identified the IRE1/XBP1 branch of the Unfolded Protein Response (UPR) or endoplasmic reticulum (EnR) stress response as a previously unexplored therapeutic vulnerability in MYC-driven breast cancer that enhances chemotherapy sensitivity and reverses the immunosuppressive tumor microenvironment. IRE1 is amplified in ~10% of human breast cancer, and frequently co-amplified with the MYC oncogene. Activation of MYC is synthetic lethal with IRE1/XBP1 pathway inhibition. We found that inhibition of the IRE1/XBP1 pathway with a highly selective first-in-class IRE1 RNase inhibitor ORIN1001 suppresses MYC-high-expressing (MYChigh), but not MYC-low-expressing (MYClow), tumor growth in patient-derived xenograft (PDX) models. ORIN1001 substantially enhances the docetaxel efficacy, resulting in rapid tumor regression and complete eradication of the MYChigh PDX tumors. Furthermore, the ORIN1001 plus docetaxel therapy triggers massive cytotoxic T-cell infiltration, depletion of immunosuppressive myeloid-derived suppressor cells (MDSCs) and substantial upregulation of PD-L1 in the tumor microenvironment. Non-human primate toxicology testing showed that ORIN1001 has excellent safety profile and is well-tolerated. The therapeutic effect of ORIN1001 is associated with a marked increase in taxane sensitivity. In addition, MDSCs are also selectively depleted by ORIN1001 in the presence of a taxane, thus reversing immunosuppression and potentially sensitizing MYChigh breast cancers to immune checkpoint intervention. A pre-clinical phase study in breast cancer models will be conducted in parallel with a Phase 1 clinical trial.
Here is a link to the trial, very few exclusions...
https://clinicaltrials.gov/ct2/show/NCT03950570#co...
PS For those interested, here is a summary of their earliest trial results:
https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.1...
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Cure-ious Hopefully, Baylor will respond to my MO that I qualify for that one. Meanwhile, she’s sending my records to Medical City Mary Crowley Research Department too.
Thanks for researching for me. I appreciate it
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One drug that sounds very promising is Erso. The only thing that's discouraging is how slowly things move to trial. It would be good for all with stage 4 ER+ cancer to keep the conversation going on it and bombard everyone involved with questions and interest. Maybe start movements and go to the media to fast track it. Wouldn't it be great if all these drugs that prolong our lives for months could be replaced by a possible cure?. It must look pretty hopeful if Bayer bought the rights to it already.
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OMG! Thanks for sharing, Elena.
Here's an article about ErSO: https://news.illinois.edu/view/6367/339688859
It could take years so we have to stay alive for it.
Hugs, Susan
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This ErSO sounds amazing ! Does anyone know the time line of mice trials to human clinical trials ? I know it's years....but this one really gives me some hope !
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Looks like the Enobosarm trial has started recruiting!
https://clinicaltrials.gov/ct2/show/NCT04869943#contacts
Wish I could be on it. Can't have been on more than one chemotherapy. I'm on my third.
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